Campylobacter jejuni is the leading bacterial cause of human enteritis in the United States. Contaminated poultry meats are considered a significant source for human Campylobacter infections. Increasing resistance of C. jejuni to clinical antibiotics poses a significant threat to public health and raises an urgent need for alternative strategies to prevent and control Campylobacter infections. Antimicrobial peptides (AMPs) are short and bactericidal peptides widely present in intestine to limit bacterial infections and also increasingly recognized as a novel class of antibiotics (peptide antibiotics) to control foodborne pathogens. Notably, several potent anti-Campylobacter bacteriocins, a group of AMPs produced by commensal bacteria, dramatically reduced C. jejuni colonization in chickens and are being directed toward on-farm control of this pathogen to protect public health. As an important strategy to evade killing by potential peptide antibiotics and by host innate defense, AMP resistance mechanisms in C. jejuni are critical to understand, but are still unknown. Our preliminary studies showed that Campylobacter could develop resistance to AMPs including the bacteriocins. We have also identified a panel of genes required for AMP resistance in C. jejuni using functional genomic approaches. Based on these observations, we hypothesize that Campylobacter has evolved complex mechanisms to develop AMP resistance and counteract killing by AMPs from various sources. To test our hypothesis, we plan to i) systematically identify and characterize genetic loci involved in C. jejuni resistance to AMPs using random transposon mutagenesis and whole genome microarray;and ii) determine the direct effect of therapeutic usage of bacteriocin on the emergence and persistence of bacteriocin-resistant Campylobacter using chicken model systems. It is anticipated that the proposed studies will enable us to develop more sustainable peptide antibiotics, provide insights into the delicate interplay between Campylobacter and the host, and ultimately lead to effective intervention strategies to prevent and control Campylobacter infections in humans. PUBLIC HEALTH RELEVANCE: Campylobacter jejuni is the most prevalent foodborne bacterial pathogen causing human gastroenteritis in the U.S. The proposed research will provide novel information on the development of effective intervention strategies against C. jejuni to protect food safety and public health.